This Program Project is structured to examine each component of the oxygen transport system which begins with ventilation of the lung under the Control of Breathing (Project A). Within the lung, the distribution of air should be matched by the distribution of blood, i.e. the Control of the Pulmonary Circulation (Project B). Actual transfer of oxygen occurs at the alveolus where control of capillary perfusion is of prime importance, and is the focus of study of the Pulmonary Microcirculation (Project C). Once oxygenated, blood circulation is determined by function of the heart and systemic circulation. Finally, the actual delivery of oxygen is dependent upon both blood oxygen content and blood flow. Oxygen content is directly related to the oxygen carrying capacity of the blood, i.e., hemoglobin concentration and hematocrit, whereas blood flow is inversely related to hematocrit (visocosity). These interrelationships and associated factors determine Systemic Oxygen Delivery (new Project D). Since the oxygen transport system must respond to changes in both oxygen supply and demand, it is of importance to understand the special adaptations to the chronic hypoxia of High Altitude (Project E). These, then, are the five major areas of investigation within this Program Project. The roles of hypotoxic and hypercapnic ventilatory drives in controlling breathing in respiratory failure, during sleep, and during exercise, are being studied. Bulk flow of CO2 to the lung will be examined as a major stimulus to hyperpnea during exercise. Histamine, prostaglandins, perivascular mast cells, and the direct effects of hypoxia are under investigation relative to pulmonary vascular control. Resulting changes in vascular tone alter the dynamics of capillary blood flow. Factors causing pulmonary capillary recruitment as a means of enhancing gas exchange will be studied. All of these mechanisms will be related to adaptation and maladaptation to High Altitude, including pregnancy, chronic mountain sickness, high altitude pulmonary edema, and oxygen transport, particularly in the presence of polycythemia.